Abstract:

A pharmaceutical dosage form comprising a controlled release component
comprising an antihyperglycemic drug in combination with a second
component comprising a thiazolidinedione derivative is herein disclosed
and described.

Claims:

1-31. (canceled)

32. A method for preparing a sustained release oral tablet comprising:a)
forming a controlled release metformin hydrochloride tablet comprising
500 mg to 1000 mg of metformin;b) preparing an immediate release coating
solution comprising:i) pioglitazone hydrochloride;ii) water;iii) an
organic solvent;iv) a binder;v) optionally a surfactant;vi) optionally a
pore forming agent wherein the ratio of water to organic solvent is 50:50
to 2:98 and the ratio of binder to pioglitazone hydrochloride is 1:9 to
1:11;b) applying the immediate release coating solution to the controlled
release metformin hydrochloride tablet so that when tested in a United
States Pharmacopeia (USP) Type 2 apparatus at 75 rpm in 900 ml of
simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37.degree.
C., not less than 75% of the pioglitazone hydrochloride is released from
the sustained release tablet in 30 minutes.

33. The method of claim 32 wherein not less than 95% of the pioglitazone
hydrochloride in released from the sustained release tablet in 30
minutes.

35. The method of claim 32 wherein the sustained release tablet is
prepared without a gelling polymer.

36. The method of claim 32 wherein the controlled release metformin
hydrochloride tablet is formed by:A) mixing the metformin hydrochloride
with at least one pharmaceutically acceptable excipient;B) compressing
the mixture of step (A) into a tablet; andC) coating the tablet of step
(B) with a membrane.

37. A tablet prepared by the method of claim 32.

38. A method for preparing a sustained release oral tablet comprising:i)
forming a controlled release metformin hydrochloride tablet comprising
500 mg to 1000 mg of metformin and without a gelling polymer comprising
the steps of:a) mixing the metformin hydrochloride with at least one
pharmaceutically acceptable excipient;b) compressing the mixture of step
(a) into a tablet; andc) coating the tablet of step (b) with a
membrane;ii) preparing an immediate release coating solution
comprising:a) pioglitazone hydrochloride;b) water;c) an organic solvent
selected from acetone, isopropyl alcohol, methanol or ethanol;d) a
binder;e) optionally a surfactant;f) optionally a pore forming agent
wherein the ratio of water to organic solvent is 50:50 to 2:98 and the
ratio of binder to pioglitazone hydrochloride is 1:9 to 1:11;c) applying
the immediate release coating solution to the membrane of the controlled
release metformin hydrochloride tablet so that when tested in a United
States Pharmacopeia (USP) Type 2 apparatus at 75 rpm in 900 ml of
simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37.degree.
C., not less than 95% of the pioglitazone hydrochloride is released from
the sustained release tablet in 30 minutes.

[0002]The present invention relates to a pharmaceutical dosage form
comprising an antihyperglycemic drug, in combination with a
thiazolidinedione derivative. More specifically, the present invention
relates to an oral dosage form comprising a biguanide e.g. metformin or
buformin or a pharmaceutically acceptable salt thereof e.g., metformin
hydrochloride or the metformin salts described in U.S. Pat. Nos.
3,957,853 and 4,080,472 which are incorporated herein by reference in
combination with a thiazolidinedione derivative as described in U.S. Pat.
No. 4,687,777 also incorporated herein by reference.

[0003]Many techniques have been used to provide controlled and
extended-release pharmaceutical dosage forms in order to maintain
therapeutic serum levels of medicaments and to minimize the effects of
missed doses of drugs caused by a lack of patient compliance.

[0004]For example, extended release tablets have been described which have
an osmotically active drug core surrounded by a semi-permeable membrane.
These tablets function by allowing the aqueous components of a fluid such
as gastric or intestinal fluid to permeate the coating membrane and
dissolve the active ingredient so the resultant drug solution can be
released through a passageway in the coating membrane. Alternatively, if
the active ingredient is insoluble in the permeating fluid, it can be
pushed through the passageway by an expanding agent such as a hydrogel.
Some representative examples of these osmotic tablet systems can be found
in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and
4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device wherein the
active agent is released from a core surrounded by a semipermeable
membrane only after sufficient pressure has developed within the membrane
to burst or rupture the membrane at a weak portion of the membrane.

[0005]The basic osmotic device described in the above cited patents have
been refined over time in an effort to provide greater control of the
release of the active ingredient. For example, U.S. Pat. Nos. 4,777,049
and 4,851,229 describe osmotic dosage forms comprising a semipermeable
wall surrounding a core. The core contains an active ingredient and a
modulating agent wherein the modulating agent causes the active
ingredient to be released through a passageway in the semipermeable
membrane in a pulsed manner. Further refinements have included
modifications to the semipermeable membrane surrounding the active core
such as varying the proportions of the components that form the membrane,
e.g. U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 or increasing the
number of coatings surrounding the active core, e.g. U.S. Pat. Nos.
5,650,170 and 4,892,739.

[0006]Certain controlled or sustained release formulations that employ
antihyperglycemic drugs such as metformin hydrochloride have been limited
to the use of an expanding or gelling agent to control the release of the
drug from the dosage form. This limited research is exemplified by the
teachings of WO 96/08243 and by the GLUCOPHAGE® XR product insert
which is a controlled release metformin HCl product commercially
available from Bristol-Myers Squibb Co.

[0007]Thiazolidinedione derivatives have been described in U.S. Pat. No.
4,687,777. The therapeutic value of these compounds in combination
therapy has further been described in U.S. Pat. Nos. 5,859,037;
5,952,356; 5,965,584; 6,150,384 and 6,172,090. However, none of these
patents describe a dosage form having the advantages of the subject
invention.

[0008]Pharmaceutical dosage forms containing combinations of
antihyperglycemic drugs and thiazolidinedione derivatives have been
proposed in the art. For example, EPO 0 749 751 (which is incorporated
herein by reference) teaches pharmaceutical compositions comprising an
insulin sensitivity enhancer, which could be a thiazolidinedione
compound, in combination with other antidiabetics. More specifically, EPO
0 749 751 teaches that the preferred insulin sensitivity enhancer is
pioglitazone, which can be combined with other antidiabetics such as
metformin, phenformin or buformin, and further that these drugs can be
associated (mixed and/or coated) with conventional excipients to provide
taste masking or sustained release. Another example of a combination of
antihyperglycemic drugs and thiazolidinedione derivatives is U.S. Pat.
No. 6,011,049, (which is incorporated herein by reference). This patent
teaches a single pharmaceutical composition that contains pioglitazone or
trolitazone and metformin in slow release forms such as osmotic pumps or
skin patches. Other combinations of antihyperglycemic drugs and
thiazolidinedione derivatives can be found in U.S. Pat. Nos. 6,524,621;
6,475,521; 6,451,342 and 6,153,632 and PCT patent applications WO
01/35940 and WO 01/35941, which are incorporated herein by reference.

[0009]Also known in the art is WO 99/47125 and U.S. Pat. No. 6,099,862
that disclose a metformin osmotic tablet coated with an immediate release
coating containing an antihyperglycemic or an hypoglycemic drug.

[0010]Although the prior art teaches pharmaceutical dosage formulations
that contain both an antihyperglycemic compound and thiazolidinedione
derivatives, the present invention provides numerous benefits over the
prior art teachings as will be described below.

[0011]It is an object of the present invention to provide a dosage form
comprising a first active drug, which is formulated to provide a
controlled or sustained release delivery. Preferably, the first active
drug is an antihyperglycemic compound. The present invention further
provides for a second active drug which preferably is a thiazolidinedione
derivative. The novel dosage form described herein provides for delivery
of first and second active drugs such that the bioavailability of either
drug is not decreased by the presence of food.

[0012]It is a further object of the present invention to provide a dosage
form, as described above, comprising delivery of a first active drug as a
controlled or sustained release formulation for an antihyperglycemic
compound, wherein said controlled or sustained release mechanism is not
regulated by an expanding polymer, in combination with delivery of a
second active drug by immediate release comprising a thiazolidinedione
derivative.

[0013]It is also a further object of the present invention to provide a
dosage form as described above, comprising delivery of a first active
drug as a controlled or sustained release formulation for an
antihyperglycemic compound in combination with delivery of a second
active drug by immediate release comprising a thiazolidinedione
derivative that can provide continuous and non-pulsating therapeutic
levels of said antihyperglycemic drug to an animal or human in need of
such treatment over a eight hour to twenty-four hour period.

[0014]It is an additional object of the present invention to provide a
dosage form comprising delivery of a first active drug as a controlled or
sustained release formulation for an antihyperglycemic compound in
combination with delivery of a second active drug by immediate release
comprising a thiazolidinedione derivative that obtains peak plasma levels
of the antihyperglycemic compound approximately 8-12 hours after
administration and peak plasma levels of thiazolidinedione derivative
approximately 1-4 hours after dosing.

[0015]It is also an object of the present invention to provide a dosage
form comprising a first active drug as a controlled or sustained release
pharmaceutical core tablet having only a homogeneous osmotic core wherein
the osmotic core component may be made using ordinary tablet compression
techniques.

[0016]It is an additional object of the present invention to provide a
dosage form comprising delivery of a first active drug as a controlled or
sustained release formulation for an antihyperglycemic compound in
combination with delivery of a second active drug by immediate release
comprising a thiazolidinedione derivative that obtains peak plasma levels
of the antihyperglycemic compound approximately 8-12 hours after
administration and peak plasma levels of thiazolidinedione derivative
approximately 1-12 hours after dosing.

SUMMARY OF THE INVENTION

[0017]The present invention relates to a pharmaceutical dosage form
comprising a first active drug, preferably an antihyperglycemic drug, in
combination with a second active drug, preferably a thiazolidinedione
derivative. More specifically, the present invention relates to an oral
dosage form comprising a first active drug comprising a biguanide such as
metformin or buformin or a pharmaceutically acceptable salt thereof eg.,
metformin hydrochloride or the metformin salts, in combination with a
second active drug comprising a thiazolidinedione derivative

[0018]The foregoing objectives are met by a dosage form comprising a first
and second active drug, wherein the first active drug is formulated as a
controlled release core, preferably an osmotic tablet, with or without a
gelling or expanding polymer. The second active ingredient may be part of
the controlled release core or it may preferably be combined with the
controlled release core in a manner that provides for immediate release
of the second active ingredient. For example, the second active
ingredient can be incorporated into a semipermeable membrane that is
applied to the core or the second active ingredient may be applied to a
coated or uncoated controlled release core.

[0019]In one embodiment the second active drug, which may be the
thiazolidinedione derivative, is provided as an immediate release
formulation in the dosage form whereas the antihyperglycemic component is
provided as a controlled release formulation in the dosage form. This
immediate release portion of the formulation should provide peak plasma
levels (Tmax) of 1-12 hours preferably, 1-4 hours of the
thiazolidinedione derivative, while the controlled release portion of the
formulation may provide peak plasma levels (Tmax) of 8-12 hours of
the antihyperglycemic component.

[0020]Preferably, the dosage form according to the subject invention may
be administered once a day, preferably with or after a meal, and most
preferably with or after the evening meal. The subject dosage form can
provide therapeutic levels of the drug throughout the day with peak
plasma levels (Tmax) of the antihyperglycemic drug being obtained
between 8-12 hours after administration.

DETAILED DESCRIPTION OF THE INVENTION

[0021]The subject invention concerns a pharmaceutical formulation or
dosage form comprising a first active drug comprising an
antihyperglycemic drug in combination with a second active drug
comprising a thiazolidinedione derivative. Preferably, the
antihyperglycemic drug is a biguanide e.g. metformin or buformin or a
pharmaceutically acceptable salt thereof. The antihyperglycemic drug is
delivered in a controlled release manner from a tablet core, preferably
an osmotic tablet core with or without a gelling or swelling polymer. The
tablet core should include the antihyperglycemic drug and at least one
pharmaceutically acceptable excipient. In one embodiment of the present
invention the tablet core includes the antihyperglycemic drug, a binding
agent and an absorption enhancer, and the tablet core is preferably
coated with a polymeric coating to form a semi-permeable membrane around
the tablet and drilled to create one passageway on each side of the
membrane. The second active drug comprises a thiazolidinedione
derivative, and is preferably applied to the membrane of the tablet core
and provides for either immediate or controlled release of said
thiazolidinedione derivative.

[0022]The term, antihyperglycemic drugs as used in this specification,
refers to drugs that are useful in controlling or managing
noninsulin-dependent diabetes mellitus (NIDDM). Antihyperglycemic drugs
include the biguanides such as metformin, phenformin or buformin or the
like, and pharmaceutically acceptable salts, isomers or derivatives
thereof.

[0023]The term thiazolidinedione derivative as used in this specification
refers to drugs that are useful for controlling or managing NIDDM. These
include, but are not limited to, troglitazone, rosiglitazone,
pioglitazone, ciglitazone or the like, and pharmaceutically acceptable
salts, isomers or derivatives thereof.

[0024]The term binding agent refers to any conventionally known
pharmaceutically acceptable binder such as polyvinyl pyrrolidone,
hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl
methylcellulose, ethylcellulose, polymethacrylate, polyvinylalcohol,
waxes and the like. Mixtures of the aforementioned binding agents may
also be used. The preferred binding agents are water soluble materials
such as polyvinyl pyrrolidone having a weight average molecular weight of
25,000 to 3,000,000. The binding agent may comprise approximately about 0
to about 40% of the total weight of the core and preferably about 3% to
about 15% of the total weight of the core. In one embodiment, the use of
a binding agent in the core is optional.

[0025]In a preferred embodiment, the core may optionally comprise an
absorption enhancer. The absorption enhancer can be any type of
absorption enhancer commonly known in the art such as a fatty acid, a
surfactant, a chelating agent, a bile salt or mixtures thereof. Examples
of some preferred absorption enhancers are fatty acids such as capric
acid, oleic acid and their monoglycerides, surfactants such as sodium
lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents
such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA)
and ethylene glycol-bis(β-aminoethyl ether)-N,N,N,N-tetraacetic acid
(EGTA). The core may comprise approximately 0 to about 20% of the
absorption enhancer based on the total weight of the core and most
preferably about 2% to about 10% of the total weight of the core.

[0026]In one embodiment of the present invention, which does not employ a
gelling or swelling polymer, the core of the present invention is
preferably formed by granulating an antihyperglycemic drug with a binding
agent and compressing the granules with the addition of a lubricant and
absorption enhancer into a tablet. The core may also be formed by dry
granulating the core ingredients by passing them through a roller
compactor and compressing the granules with the addition of a lubricant
into tablets. Direct compression may also be employed for tabletting.
Other commonly known granulation procedures are known in the art.
Additionally, other excipients such as lubricants, pigments or dyes may
also be employed in the formulation of the subject invention.

[0027]The term gelling or swelling polymer refers to polymers that gel,
swell or expand in the presence of water or biological fluids.
Representative examples of gelling or swelling polymers are high
molecular weight hydroxpropyl methylcellulose (such as METHOCEL®
K100M, which is commercially available from Dow Chemical) and high
molecular weight polyethylene oxides (such as POLYOX WSR 301, WSR 303 or
WSR COAGULANT). Other gelling or swelling polymers are described in U.S.
Pat. No. 4,522,625 (which is incorporated herein by reference).

[0028]The core formed as described herein, can be coated with a membrane,
preferably a semipermeable polymeric coating. The semipermeable membrane
is permeable to the passage of an external fluids such as water or
aqueous biological fluids and is impermeable to the passage of the
antihyperglycemic drug in the core. Materials that are useful in forming
the semipermeable membrane are ethylcellulose, cellulose esters,
cellulose diesters, cellulose triesters, cellulose ethers, cellulose
ester-ether, cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate,
cellulose acetate propionate and cellulose acetate butyrate. Other
suitable polymers are described in U.S. Pat. Nos. 3,845,770; 3,916,899;
4,008,719; 4,036,228 and 4,612,008 (which are incorporated herein by
reference). The most preferred semipermeable membrane material is
cellulose acetate comprising an acetyl content of 39.3 to 40.3%, and is
commercially available from Eastman Fine Chemicals.

[0029]In an alternative embodiment, the semipermeable membrane can include
one of the above-described polymers and a flux-enhancing agent. The flux
enhancing agent can increase the volume of fluid imbibed into the core to
enable the dosage form to dispense substantially all of the
antihyperglycemic drug through the passageway and/or the porous membrane.
The flux-enhancing agent can be a water-soluble material or an enteric
material. Examples of the preferred materials that are useful as flux
enhancers are sodium chloride, potassium chloride, sucrose, sorbitol,
mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl
cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose
phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic
acid copolymers, poloxamers (such as LUTROL F68, LUTROL F127, LUTROL F108
which are commercially available from BASF) and mixtures thereof. A
preferred flux-enhancer is PEG 400.

[0030]The flux enhancer may also be a drug that is water soluble such as
metformin or its pharmaceutically acceptable salts, or the flux enhancer
may be a drug that is soluble under intestinal conditions. If the flux
enhancer is a drug, the present dosage form has the added advantage of
providing an immediate release of the drug, that has been selected as the
flux enhancer.

[0031]The flux enhancing agent comprises approximately 0 to about 40% of
the total weight of the coating, most preferably about 2% to about 20% of
the total weight of the coating. The flux enhancing agent dissolves or
leaches from the semipermeable membrane to form paths in the
semipermeable membrane which enables fluid to enter the core and dissolve
the active ingredient.

[0032]The semipermeable membrane may also be formed using a commonly known
excipient such as a plasticizer. Some commonly known plasticizers include
adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,
triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric
acid esters, and those described in the Encyclopedia of Polymer Science
and Technology, Vol. 10 (1969), published by John Wiley & Sons. The
preferred plasticizers are triacetin, acetylated monoglyceride, grape
seed oil, olive oil, sesame oil, acetyltributylcitrate,
acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate,
diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate,
dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate
and the like. Depending on the particular plasticizer, amounts from about
0 to about 25%, and preferably about 2% to about 15% of the plasticizer
can be used based upon the total weight of the coating.

[0033]Generally, the membrane coating around the core will comprise from
about 1% to about 5% and preferably about 2% to about 3% based upon the
total weight of the core and coating.

[0034]In a preferred embodiment, the membrane coating surrounding the core
further comprises a passageway that will allow for controlled release of
the drug from the core. As used herein the term passageway includes an
aperture, orifice, bore, hole, weakened area or an erodible element such
as a gelatin plug that erodes to form an osmotic passageway for the
release of the antihyperglycemic drug from the dosage form. Passageways
used in accordance with the subject invention are well known and are
described in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407;
4,783,337 and 5,071,607.

[0035]Independent of the antihyperglycemic is a second active drug,
preferably a thiazolidinedione derivative. This second active drug may be
formulated to provide an immediate release of the thiazolidinedione
derivative. In one embodiment of the present invention the
thiazolidinedione derivative is applied in the form of a layer to a
controlled or sustained released core comprising the antihyperglycemic
drug as a layer using a binder and other conventional pharmaceutical
excipients such as absorption enhancers, surfactants, plasticizers,
antifoaming agents and combinations of the foregoing. An absorption
enhancer may be present in the thiazolidinedione derivative layer in an
amount up to about 30% w/w in comparison to the weight of the
thiazolidinedione derivative. A binding agent may be present in an amount
up to 150% w/w of the thiazolidinedione derivative. A second active drug
immediate release formulation may be incorporated into a single dosage
form by coating onto the semipermeable membrane of the dosage form by
conventional methods. Alternatively, it may be incorporated by any
pharmaceutically acceptable method into a single dosage form with the
first active drug. The incorporation of the second active drug may be
performed by, but would not be limited to, the processes selected from
the group consisting of drug layering, lamination, dry compression,
deposition and printing.

[0036]When the thiazolidinedione derivative is coated onto a semipermeable
membrane of an osmotic tablet core, the thiazolidinedione coating should
be applied from a coating solution or suspension that employs an aqueous
solvent, an organic solvent or a mixture of an aqueous and an organic
solvent. Typical organic solvents include acetone, isopropyl alcohol,
methanol and ethanol. If a mixture of aqueous and organic solvents is
employed, the ratio of water to organic solvent should range from 98:2 to
2:98, preferably 50:50 to 2:98. If a mixed solvent system is employed,
the amount of binder required for coating the thiazolidinedione
derivative onto the semipermeable membrane may be reduced. For example,
successful coatings have been obtained from a mixed solvent system where
the ratio of binder to thiazolidinedione derivative is 1:9 to 1:11.
Although acceptable coatings can be obtained when the thiazolidinedione
coat is applied directly to the semipermeable, a preferred approach is to
first coat the semipermeable membrane with a seal coat prior to the
application of the thiazolidinedione coating. As used herein a seal coat
is a coating that does not contain an active pharmaceutical ingredient
and that rapidly disperses or dissolves in water.

[0038]In an alternative embodiment, the dosage form of the present
invention may also comprise an effective immediate release amount of the
antihyperglycemic drug. The effective immediate release amount of
antihyperglycemic drug may be coated onto the semipermeable membrane of
the dosage form or it may be incorporated into the semipermeable
membrane.

[0039]In addition, various diluents, excipients, lubricants, dyes,
pigments, dispersants, etc., which are disclosed in Remington's
Pharmaceutical Sciences (1995), may be used to optimize the above listed
formulations of the subject invention.

[0042]The dosage forms prepared according to the present invention exhibit
the following dissolution profile when tested in a USP Type 2 apparatus
at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate
buffer) and at 37° C.:

[0045]The metformin HCl is delumped by passing it through a 40 mesh screen
and collecting it in a clean, polyethylene-lined container. The povidone,
K-30, and sodium tribasic phosphate are dissolved in purified water. The
delumped metformin HCl is then added to a top-spray fluidized bed
granulator and granulated by spraying the binding solution of povidone
and sodium tribasic phosphate under the following conditions: inlet air
temperature of 50-70° C.; atomization air pressure of 1-3 bars and
spray rate of 10-100 ml/min.

[0046]Once the binding solution is depleted, the granules are dried in the
granulator until the loss on drying is less than 2%. The dried granules
are passed through a comil equipped with the equivalent of an 18 mesh
screen.

(b) Tableting

[0047]The magnesium stearate is passed through a 40 mesh stainless steel
screen and blended with the metformin HCl granules for approximately five
(5) minutes. After blending, the granules are compressed on a rotary
press fitted with 15/32'' round standard concave punches (plain lower
punch, upper punch with an approximately 1 mm indentation pin).

[0048]As stated above, the orifice may be formed by any means commonly
employed in the pharmaceutical industry.

(c) Seal Coating (optional)

[0049]The core tablet can be seal coated with an Opadry material or other
suitable water-soluble material by first dissolving the Opadry material,
preferably Opadry Clear, in purified water. The Opadry solution is then
sprayed onto the core tablet using a pan coater under the following
conditions: exhaust air temperature of 38-42° C.; atomization
pressure of 28-40 psi and spray rate of 10-15 ml/min. The core tablet is
coated with the sealing solution until a theoretical coating level of
approximately 2-4% is obtained.

[0050]The cellulose acetate is dissolved in acetone while stirring with a
homogenizer. The polyethylene glycol 400 and triacetin are added to the
cellulose acetate solution and stirred until a clear solution is
obtained. The clear coating solution is then sprayed onto the seal coated
tablets in a fluidized bed coater employing the following conditions:
product temperature of 16-22° C.; atomization pressure of
approximately 3 bars and spray rate of 120-150 ml/min. The sealed core
tablet is coated until a theoretical coating level of approximately 3% is
obtained.

[0051]Tween 80 and hydroxypropyl methylcellulose are dissolved in purified
water. Pioglitazone HCl is then dispersed into this solution. The
resulting suspension is then sprayed onto the above-described tablets.

[0053]The metformin HCl and sodium lauryl sulfate are delumped by passing
them through a 40 mesh screen and collecting them in a clean,
polyethylene-lined container. The povidone, K-90, is dissolved in
purified water. The delumped metformin HCl and sodium lauryl sulfate are
then added to a top-spray fluidized bed granulator and granulated by
spraying with the binding solution of povidone under the following
conditions: inlet air temperature of 50-70° C.; atomization air
pressure of 1-3 bars and spray rate of 10-100 ml/min.

[0054]Once the binding solution is depleted, the granules are dried in the
granulator until the loss on drying is less than 2%. The dried granules
are passed through a comil equipped with the equivalent of an 18 mesh
screen.

(b) Tableting

[0055]The magnesium stearate is passed through a 40 mesh stainless steel
screen and blended with the metformin HCl granules for approximately five
(5) minutes. After blending, the granules are compressed on a rotary
press fitted with 15/32'' round standard concave punches (plain lower
punch, upper punch with an approximately 1 mm indentation pin).

[0056]As stated above, the orifice may be formed by any means commonly
employed in the pharmaceutical industry.

(c) Seal Coating (optional)

[0057]The core tablet can be seal coated with an Opadry material or other
suitable water-soluble material by first dissolving the Opadry material,
preferably Opadry Clear in purified water. The Opadry solution is then
sprayed onto the core tablet using a pan coater under the following
conditions: exhaust air temperature of 38-42° C.; atomization
pressure of 28-40 psi and spray rate of 10-15 ml/min. The core tablet is
coated with the sealing solution until a theoretical coating level of
approximately 2% is obtained.

[0058]The cellulose acetate is dissolved in acetone while stirring with a
homogenizer. The polyethylene glycol 400 and triacetin are added to the
cellulose acetate solution and stirred. The coating solution is then
sprayed onto the seal coated tablets in a fluidized bed coater employing
the following conditions: product temperature of 16-22° C.;
atomization pressure of approximately 3 bars and spray rate of 120-150
ml/min. The sealed core tablet is coated until a theoretical coating
level of approximately 3% is obtained.

Tween 80 and hydroxypropyl methylcellulose are dissolved in purified
water. Pioglitazone HCl is then dispersed into this solution. The
resulting suspension is then sprayed onto the above described tablets.

[0062]The pioglitazone coating is directly applied to the 500 mg metformin
HCl osmotic tablets. The pioglitazone coating is prepared by dissolving
0.252 kg of Opadry Clear, 0.269 kg of Polyplasdone XL and 0.036 kg of
Tween 80 in 9.908 kg of purified water using a homogenizer. Once these
ingredients are dissolved, 0.296 kg of pioglitazone HCl is dispersed into
the solution and homogenized. The homogenized dispersion is then directly
applied to the 500 mg metformin HCl osmotic tablets using a 24''O'Hara
Labcoat III pan coater with the following conditions:

[0063]Once the pioglitazone coating has been applied to the 500 mg
metformin HCl osmotic tablet core, an aesthetic or color coating of
Opadry white is applied to the pioglitazone coated tablet. The color
coating is prepared by dispersing 0.179 kg of Opadry White in 1.791 kg of
purified water. The Opadry White suspension is applied to the
pioglitazone coated tablet using a 24'' O'Hara Labcoat III pan coater
under the following conditions:

[0069]The pioglitazone coating is applied to the seal coated 500 mg
metformin HCl osmotic tablets. The pioglitazone coating is prepared by
dissolving 0.040 kg of Opadry Clear, 0.085 kg of sodium chloride and
0.040 kg of Tween 80 in 4.915 kg of purified water using a homogenizer.
Once these ingredients are dissolved, 0.328 kg of pioglitazone HCl is
dispersed into the solution and homogenized. The homogenized dispersion
is then applied to the seal coated 500 mg metformin HCl osmotic tablets
using a 24'' Ohara Labcoat III pan coater with the following conditions:

[0070]Once the pioglitazone coating has been applied to the seal coated
500 mg metformin HCl osmotic tablets, an aesthetic or color coating of
Opadry white is applied to the pioglitazone coated tablet. The color
coating is prepared by dispersing 0.159 kg of Opadry White in 1.585 kg of
purified water. The Opadry White suspension is applied to the
pioglitazone coated tablet using conditions similar to those described
above for application of the seal coating. Once the color coating is
applied, the tablets are polished using 0.004 kg of Candelilla wax
powder.

[0075]The pioglitazone coating then is applied to the seal coated 1000 mg
metformin HCl osmotic tablets. The pioglitazone coating is prepared by
dissolving 0.036 kg of Opadry Clear and 0.046 kg of sodium chloride in
5.344 kg of ethanol using a homogenizer. Once the ingredients are
dispersed, 0.359 kg of pioglitazone HCl is dispersed into the solution
and homogenized. The homogenized dispersion is then applied to the seal
coated 1000 mg metformin HCl cellulose acetate coated tablets using a
24'' O'Hara Labcoat III pan coater with the following conditions:

[0076]Once the pioglitazone coating has been applied, an aesthetic or
color coating of Opadry II White is applied to the pioglitazone coated
tablets. The color coating is prepared by dispersing 0.220 kg of Opadry
II White in 4.407 kg of ethanol. The Opadry II White suspension is then
applied to the pioglitazone HCl coated tablets using a 24'' O'Hara
Labcoat III pan coater using conditions similar to those described above
for the seal coating. Once the color coating is applied, the tablets are
polished using 0.004 kg of Candelilla wax powder.

[0080]The seal coat is applied to the 1000 mg metformin HCl osmotic
tablet. The seal coating is prepared by dispersing 0.229 kg of Opadry
Clear in 4.573 kg of alcohol USP and mixing the dispersion for 15
minutes. The dispersion is then sprayed onto approximately 13.08 kg of
the 1000 mg metformin HCl tablet cores using a 24'' Ohara Labcoat III pan
coater with the nozzle tip set 4±2'' from the top of the static bed
and the following conditions:

[0081]The seal coating dispersion is continuously stirred until it is
consumed during the coating process.

[0082]The pioglitazone coating then is applied to the seal coated 1000 mg
metformin HCl osmotic tablets. The pioglitazone coating is prepared by
mixing 4.434 kg of alcohol USP and 1.250 kg of purified water and slowly
dispersing 0.040 kg of Opadry Clear into the solvent mixture. Once the
Opadry Clear is dispersed, it is homogenized for about 10 minutes. Once
the Opadry Clear dispersion is homogenized, 0.054 kg of sodium chloride
is added to the dispersion and homogenized for about 2 minutes. After the
sodium chloride is homogenized, 0.360 kg of pioglitazone HCl is slowly
dispersed into the solvent mix and then homogenized for about 10 minutes.
Once the pioglitazone HCl is homogenized, the homogenizer is removed from
the mixing vessel and replaced with an air mixer and mixed for an
additional 15 minutes. The pioglitazone suspension is stirred until the
suspension is consumed during the coating process. The pioglitazone HCl
suspension is applied to the seal coated 1000 mg metformin HCl osmotic
tablet cores using a 24'' Ohara Labcoat III pan coater with the nozzle
tip set 4±2'' above the top of the static bed with the following
conditions:

[0083]Once the pioglitazone coating has been applied to the seal coated
1000 mg metformin HCl osmotic tablets, an aesthetic coating of Opadry II
White is applied to the pioglitazone coated tablet. The aesthetic coating
is prepared by dispersing 0.235 kg of Opadry II White (Y-22-7719) in
4.691 kg of alcohol USP and mixing the dispersion for about 1 hour. The
Opadry II White dispersion is then sprayed onto the pioglitazone HCl
coated tablets using a 24'' Ohara Labcoat III pan coater with the nozzle
tip set 4±2'' from the top of the static bed and the following
conditions:

[0084]The color coating dispersion is continuously stirred until the
dispersion is consumed during the coating process.

[0085]Once the aesthetic coating suspension is consumed, the tablets are
dried in the coating pan for about 5 minutes with a pan speed of about
2-8 rpms and an exhaust temperature of 25±5° C. Once the
tablets are dried, the exhaust air is turned off and the pan speed is
adjusted to about 3-4 rpms and 0.004 kg of Candellia wax powder that had
been passed through a 60 mesh screen is sprinkled onto the tablets. After
the tablets have rolled in the wax for about 5 minutes the exhaust air is
turned on and the tablets are rolled for an additional 10 minutes.

[0086]The final polished tablet exhibits the following pioglitazone HCl
dissolution profile when tested in a USP apparatus type 1 at 100 rpm in a
pH 2.0 HCl-0.3M KCl buffer solution:

[0087]While certain preferred and alternative embodiments of the invention
have been set forth for purposes of disclosing the invention,
modifications to the disclosed embodiments may occur to those who are
skilled in the art. Accordingly, the appended claims are intended to
cover all embodiments of the invention and modifications thereof which do
not depart from the spirit and scope of the invention.